Antihyperlipidemic Drugs Part 3

Front 1

What are the important inhibitors of intestinal cholesterol absorption?

Back 1

Ezetimibe

Front 2

Describe ezetimibe

Back 2

-A specific inhibitor of intestinal absorption of cholesterol and plant sterols
-Reduces LDL levels
-Useful in monotherapy for patients who cannot tolerate statins or in combination with statins
-Reduces LDL by about 18%
-Increased HDL 3%
-No significant effect on trigluceride levels
-No evidence that it reduces CHD risk

Front 3

Describe the mechanism of ezetimibe

Back 3

-Interferes with cholesterol absorption in the small intestine
-The molecular target is a specific brush border protein that is involved in cholesterol transport for the intestinal lumen into the mucosal cell
-Reduced cholesterol absorption leads to a reduced hepatic cholesterol pool
-To try and restore hepatic cholesterol homeostasis, hepatic LDL receptor activity increases and clearance of LDL from plasma is accelerated

Front 4

How do you treat patients with a zero-cholesterol diet

Back 4

-Used Ezetimibe
-Most of the cholesterol within the intestinal lumen is of biliary origin
-Blocking intestinal absorption of cholesterol can be expected to reduce plasma LDL levels in zero-cholesterol diet patients

Front 5

Describe the effect of Ezetimibe on non-LDL substances

Back 5

-Does not cause a generalized fat malabsorption
-No effect on intenstinal absoprtion of triglyceride, vitamin A, vitamin D, bile acid, ethinylestradiol, or progesterone

Front 6

Describe what happens to ezetimibe after ingestion

Back 6

-It is converted to its glucuronide, which is more potent at inhibiting cholesterol absoprtion
-Ezetimibe glucuronide is targeted to its pharmacologic site of action by an enterohepatic circualtion and by a propensity to concentrate at the intestinal mucosal cell brush border

Front 7

Describe the excretion of ezetimibe

Back 7

-Predominantly through the intestine
-No more than 11% by the kidneys

Front 8

Describe the systemic exposure of ezetimibe

Back 8

Very low

Front 9

Describe the side effects of ezetimibe

Back 9

-Well tolerated
-No reported side effects

Front 10

What are the important Fibric Acide Derivatives?

Back 10

Gemfibrozil
Fenofibrate
Fenofibric Acid
Clofibrate

Front 11

Describe the mechanism of Fibric Acid Derivatives

Back 11

-Mediated by interactions with the peroxisome proliferator receptor alpha (PPAR-alpha)
-Some of the most important effects are
i. Increased synthesis of lipoprotein lipaase
ii. Increased synthesis of apolipoproteins AI and AII, the major proteins of HDL
iii. Increased syntehsis of the ABCA1 transporter, which promotes cholesterol efflux from cells to HDL in the process of HDL assembly
iv. Reduction of apoC-III, an inhibitor of lipoprotein lipase
v. Decreased expression of NPC1K1, a critical protein for cholesterol absoprtion (and also the pharmacological target of ezetimibe)

Front 12

What is the main pharmacological effect of fibric acid derivatives?

Back 12

To reduce levels of VLDL by enhancing its intravascular catabolism through increased lipoprotein lipase activity

Front 13

Describe the effects of Fibric Acid Derivatives

Back 13

-Increases levels of lipoprotein lipase
-Reduces LDL by ~10%
-May increase LDL in hypertriglyceridemic patients

Front 14

Describe the drug-drug interactions of Fibric Acid Derivatives

Back 14

-Potentiates the effects of warfarin by displacing it from the binding sites of albumin

Front 15

Describe the side effects of Fibric Acid Derivatives

Back 15

-GI disturbance
-Weight gain
-Decreased libido
-Drowsiness
-Skin rashes
-Alopecia
-Moderate and transient serum transaminase elevations occur but do not indicate hepatic injury
-Drugs increase lithogenicity of bile
-Usage assocaited with increased incidence of choleslithiasis and cholecystitis
-Acute myositus and cardiac ventricular irritability (rare)

Front 16

Which Fibric Acid Derivatives are prefered for use with statins?

Back 16

-Fenofibrate and Fenofibric acid
-Less potential for causing drug drug interactions

Front 17

What are the side effects of clofibrate?

Back 17

-Cardiac arrhythmias
-Cardiomegaly
-Increased angina pectoris
-Intermittent claudication
-Thromboembolic phenomena

Front 18

Which Fibric Acid Derivatives should be used in patients who have CHD?

Back 18

-Fenofibrate
-Gemfibrozil

Front 19

Who should be treated with fibrin acid drugs?

Back 19

1) Those with low HDL levels who have diabetes or the metabolic syndrome

2) Those with very high triglyceride levels

3) Those with dysbetalipiproteinemia

Front 20

Describe Long-Chain Omega-3 Fatty Acids

Back 20

-Present in fish oils
-Potent in lowering plasma VLDL levels of normal and hypertriglyceridemic patients
-Have beneficial effects on CHD and arrhythmic sudden death at much lower levels than required for lipid lowering treatment

Front 21

Describe the mechanism of Omega 3 Fatty Acids

Back 21

-Primary effect is to reduce levels of sterol receptor element binding proteins (SREBPs)
-This decreases lipogenesis and increases intracellular degradation of apoB within the hepatocyte
-This causes marked reduction in the secretion of VLDL

Front 22

Describe the effect of Omega 3 Fatty Acids on Cholesterol levels

Back 22

-Have little to no effect on LDL levels
-Cause a small reduction in HDL levels
-May increase LDL levels in hypertriglyceridemic persons

Front 23

Describe the Statin-Bile Acid Sequestrant Combination

Back 23

-Statin + Bile acid sequestrant is effective
-Activity is synergistic, Statin block the increased hepatic cholesterogenesis that occurs when a bile acid sequestrant is used

Front 24

What combinations of drugs are used to reduce LDL

Back 24

-Statin+Bile Acid Sequestrant
-Statin+Ezetimibe
-Statin+Nicotinic Acid
-Statin+Fibric Acid Derivative
-Bile acid sequestrant+Nicotinic Acid
-Statin+Bile Acid Sequestrant+Nicotinic Acid

Front 25

Describe the Statin-Nicotinic acid combination

Back 25

-Highly effective
-Combination leads to a small increase in myositis risk

Front 26

Describe the Statin-Fibric Acid Derivative combination

Back 26

Gemfibrozil
-Increased incidence of myosistis
-Less effective in reducing LDL levels

-Usually done with fenofibrate or fenofibric acid

Front 27

Describe the Bile Acid Sequestrant + Nicotinic Acid combination

Back 27

-Bile acid sequestrants enhance clearance of LDL
-Nicotinic acid decreases production of VLDL
-Combination gives additive results
-Nicotonic acid attenuates increase in VLDL levels seen in patietns treated with bile acid sequestrants

Front 28

What are the most effective medications for reducing triglyceride levels?

Back 28

-Omega 3 Fatty Acids
-Nicotinic Acid
-Fibrinc acid Derivatives

Front 29

What drugs increase HDL levels and by how much?

Back 29

-Nicotinic Acid (25-50%)
-Fibric acid drugs (10%, but greater in hypertriglyceridemic persons)
-Statins (5-10%)
-Bile acid sequestrants (2%)